The counterintuitive observation that cancer risk does not always correlate with a species’ size or longevity is known as Peto’s Paradox, named after British epidemiologist Richard Peto, who first noted the phenomenon in 1977. It turns out that cancer does not strike all species equally: Some animals have evolved powerful strategies to keep the disease at bay, while others are particularly vulnerable.
Scientists are increasingly exploring this interspecies variation in cancer rates, hoping to learn more about how cancer works in humans and to identify better ways of treating or preventing it.
“Elephants should be getting cancer all the time,” said University of Utah cancer researcher Joshua Schiffman, who has been studying the topic for the past decade. “But they don’t. They’ve evolved some really effective anti-cancer strategies.”
Schiffman — a pediatric oncologist who also treats humans with cancer — and colleagues have found that elephants have 40 copies of the TP53 gene, which suppresses tumor cells before they can grow and spread. By comparison, humans and most other animals have only two copies. Schiffman and research partner Carlo Maley of Arizona State University say they suspect that the extra copies may give elephants a powerful ability to keep mutant cells at bay. Scientists have long known that TP53 helps the body kill rogue cells before they can transform into tumors. But until Schiffman and Maley’s work, no one realized that any animal had 40 copies of the gene. The elephants’ approach appears to be a unique evolutionary strategy for fighting cancer.
Schiffman and colleagues found that elephants also have other anti-cancer mechanisms. Elephant cells respond differently when exposed to substances that damage DNA. Instead of trying to repair the damage, they tend to simply die. With cancer, this is a much safer approach: Cells that try to heal themselves are more likely to mutate and then transform into cancer cells. In a paper published in March, Schiffman and University of Utah scientist Christopher Gregg identified three genes that prevent mutations by fostering DNA repair.
Together, these genetic adjustments may give elephants multiple weapons against the disease.
Elephants are not the only animal with unusually low rates of cancer. Using data from zoos and veterinarians as well as anecdotal reports from the wild and lab research, scientists know or suspect that other creatures, including mole rats, gray squirrels, horses, whales and bats, rarely get cancer.
It is not entirely clear where humans fall on the spectrum of risk. For humans, the lifetime probability of having cancer is about 50 percent. While we do have some cancer-suppressing genes, we also tend to live for a relatively long time. For most animals, the lifetime cancer risk is probably between 20 and 40 percent, with outliers on each end — elephants on one side and dogs, mice and cheetahs on the other.
Of course, cancer is tracked much more systematically in humans than in other species. “We just don’t have that much data from nature,” said University of California at Riverside biologist Leonard Nunney, who studies evolution, animals and cancer, and coined the term “Peto’s Paradox.” “So it’s very hard to compare.”
Perhaps the strangest animal being studied for its cancer-fighting abilities is the naked mole rat, a five-inch-long, hairless, pinkish rodent that lives in burrows in East Africa. These creatures survive far longer than most rodents — up to 32 years — and seldom get tumors.
Over decades, scientists have studied thousands of naked mole rats in labs and zoos around the world; in that time, they have documented only six cases of cancer. For the past 13 years, University of Rochester scientists Vera Gorbunova and her husband, Andrei Seluanov, have been trying to unravel how the animals accomplish this.
One key may be a viscous liquid known as hyaluronic acid. Gorbunova and Seluanov have found that the animals produce large amounts of this substance, which seems to prevent tumors from growing out of control. The mechanism may involve contact inhibition, the tendency of cells to stop dividing when squeezed tightly by other cells. Cancer starts when mutated cells grow uncontrollably; by increasing contact inhibition, hyaluronic acid, which Gorbunova describes as “basically a gooey sugar,” probably keeps these tumor cells from replicating.
Naked mole rats also have other mechanisms to squelch cancer. The animals have an unusually powerful version of a gene called p16, which prevents runaway growth of tumor cells, and have also evolved a further strategy: If cancerous cells somehow get past hyaluronic acid and p16, mole rat cells have a fail-safe switch that causes tumors to essentially deactivate themselves, a state known as senescence.
Gorbunova and Seluanov also study blind mole rats, another rodent species with extremely low rates of cancer. Over decades of research on hundreds of these animals, scientists have never found a naturally occurring tumor. These creatures, which live underground and have no eyes, have evolved an anti-cancer strategy known as concerted cell death. Their cells are programmed to replicate far fewer times than those of most other species, a feature that greatly lowers the risk that mutations will run amok.
Other researchers examining certain bat species have located several tumor-suppressing genes. A recent study of the bowhead whale, which weighs up to 100 tons and can live for more than 200 years, identified several genes that probably improve the creature’s ability to repair DNA mutations. The slower metabolism of large animals such as elephants and whales may also play a role in their lower cancer rates: More-intense energy production leads to more cell division, and thus a higher risk of mutations.
Just as some creatures are more adept at fending off tumors, others are particularly vulnerable. Certain breeds of dog fall into this category: More than half of all golden retrievers die of cancer; Scottish terriers are 18 times as likely as the average dog to get bladder cancer, and Irish wolfhounds are 100 times as likely to get bone cancer.
This predisposition is due largely to the narrow level of genetic variation within most breeds, a phenomenon known as the founder effect. As inbreeding has increased over many generations, genetic abnormalities in the original population have been magnified.
This predisposition makes the animals a valuable model. “With dogs, it’s much easier to find genetic aberrations that lead to cancer,” said North Carolina State University molecular biologist Matthew Breen, who has studied canine cancer for more than two decades. “We can accelerate the discovery process.”
He has found that some kinds of cancer develop along very similar pathways in dogs and humans, and has identified several genetic mutations in dog cancers that also appear to exist in the human versions of this cancer. One of these mutations, which plays a role in 85 percent of canine bladder cancers, also exists in humans. Scientists had known about the human mutation, but Breen’s research offers a key clue about its potential significance.
This work is especially useful for cancers that are rare in humans. Take bone cancer: In the United States, about 1,000 people a year, mostly children, get the disease. By comparison, more than 50,000 dogs are diagnosed annually. Breen and his colleagues have started to identify what drives the disease in dogs and have shown that the same mutations are present in the human version. “Working with dogs, we have access to 50 times the number of patients,” he said. “This gives us a much better chance of figuring out the mechanisms of this.”
Breen is overseeing a nationwide study that is monitoring several million dogs. He travels constantly, connecting with veterinarians, dog owners and breeders, asking them to share canine cancer data. The potential pool is enormous: Every year, more than 4 million dogs in the United States are diagnosed with cancer. Eventually, he said, the database will allow scientists to delve more deeply into how, why and where dogs get cancer.
The ultimate goal is to develop new ways to fight human cancer. Eventually, it may be possible to use gene therapy, genetic engineering or pharmacology to apply animals’ cancer strategies to humans. This work has already begun: Gorbunova and Seluanov are now testing whether hyaluronic acid can prevent the disease in mice. Other anti-cancer strategies of animals have not reached the testing stage, but Schiffman said the potential is clearly there.
“This is a whole new field,” he said. “We are at the tip of the iceberg. Nature has come up with these solutions over hundreds of millions of years of evolution. Now we need to analyze that and apply it to humans.”